(1) Field of the Invention
This invention relates to a novel 7-(pyridinyl)-1-alkyl-1,4-dihydro-4-oxo-3-quinolinecarboxylic acid, salts thereof, its preparation and its antibacterial use.
(2) Information Disclosure Statement
Hepworth British Pat. No. 822,586, published October 8, 1959, shows the nitration of 1-methyl-4-quinolone-3-carboxylic acid, alternatively named 1,4-dihydro-1-methyl-4-oxo-3-quinolinecarboxylic acid, by reacting it at room temperature with a nitrating agent comprising anhydrous nitric acid together with another anhydrous mineral acid, for example, sulfuric or phosphoric acid, to produce 1-methyl-6-nitro-4-quinolone-3-carboxylic acid, alternatively named 1,4-dihydro-1-methyl-6-nitro-4-oxo-3-quinolinecarboxylic acid.
Barton et al. British Pat. No. 830,832, published Mar. 23, 1960, shows as antibacterial agents 1-alkyl-4-quinolone-3-carboxylic acids. Illustrative of compounds disclosed are 1-ethyl-6-nitro-4-quinolone-3-carboxylic acid (Example 38), which was prepared by nitrating 1-ethyl-4-quinolone-3-carboxylic acid at room temperature with a mixture of concentrated nitric acid and concentrated sulfuric acid and 1-ethyl-6-fluoro-4-quinolone-3-carboxylic acid (Example 17), alternatively named 1-ethyl-1,4-dihydro-6-fluoro-4-oxo-3-quinolinecarboxylic acid, which was prepared by heating 3-ethoxycarbonyl-6-fluoro-4-hydroxyquinoline with diethyl sulfate in aqueous sodium hydroxide solution.
Lesher and Carabateas U.S. Pat. No. 3,753,993, issued Aug. 21, 1973, shows as antibacterial agents 1-alkyl-1,4-dihydro-4-oxo-7-(pyridinyl)-3-quinolinecarboxylic acids. Illustrative of these compounds is 1-ethyl-1,4-dihydro-7-(2,6-dimethyl-4-pyridinyl)-4-oxo-3-quinolinecarboxyl ic acid (Example 6A, also known as Win 35,439), which was prepared stepwise as follows: first reacting 4-(3-aminophenyl)-2,6-dimethylpyridine with diethyl ethoxymethylenemalonate to produce diethyl 3-(2,6-dimethyl-4-pyridinyl)anilinomethylenemalonate (Example 6B), next heating the latter in an eutectic mixture of diphenyl and diphenyl ether (Dowtherm A) to produce ethyl 1,4-dihydro-7-(2,6-dimethyl-4-pyridinyl)-3-quinolinecarboxylate (Example 6C) and then heating said ester with ethyl iodide in dimethylformamide in the presence of anhydrous potassium carbonate to produce 1-ethyl-1,4-dihydro-7-(2,6-dimethyl-4-pyridinyl)-4-oxo-3-quinolinecarboxyl ic acid (Example 6A). Also shown in this patent as Example 1A is 1-ethyl-1,4-dihydro-4-oxo-7-(4-pyridinyl)-3-quinolinecarboxylic acid, now known generically as rosoxacin and also as Win 35,213.
Lesher and Carabateas U.S. Pat. No. 3,907,808, issued September 23, 1975, show as antibacterial agents 1-alkyl-1,4-dihydro-4-oxo-5(or 6)-(halo, lower-alkyl or lower-alkoxy)-7-(pyridinyl)-3-quinolinecarboxylic acids. Illustrative of these compounds is 7-(3,5-dicarboxy-2,6-dimethyl-4-pyridinyl)-1-ethyl-6-fluoro-1,4-dihydro-4- oxo-3-quinolinecarboxylic acid (Example 57A), which was prepared in six steps starting with 2-fluoro-5-nitrobenzaldehyde as follows: (1) a mixture containing 2-fluoro-5-nitrobenzaldehyde, methyl acetoacetate, methanol and concentrated ammonium hydroxide was refluxed to produce dimethyl 4-(2-fluoro-5-nitrophenyl)-1,4-dihydro-2,6-dimethyl-3,5-pyridinedicarboxyl ate (Example 57B); (2) oxidizing the product of Example 57B by heating it with 4 N nitric acid to produce dimethyl 4-(2-fluoro-5-nitrophenyl)-2,6-dimethyl-3,5-pyridinedicarboxylate (Example 57C); (3) catalytically hydrogenating Example 57C to produce dimethyl 4-(5-amino-2-fluorophenyl)-2,6-dimethyl-3,5-pyridinedicarboxylate (Example 57D); (4) reacting Example 57D with diethyl ethoxymethylenemalonate to produce 3-(3,5-dicarbomethoxy)-2,6-dimethyl-4-pyridinyl)-4-fluoroanilinomethylenem alonate (Example 57E); (5) heating Example 57E in Dowtherm A to produce ethyl 7-(3,5-dicarbomethoxy-2,6 -dimethyl-4-pyridinyl)-6-fluoro-1,4-dihydro-4-oxo-3-quinolinecarboxylate (Example 57F); and, (6) heating Example 57F with ethyl iodide in dimethylformamide in the presence of anhydrous potassium carbonate and saponifying the resulting compound to produce 7-(3,5-dicarboxy-2,6-dimethyl-4-pyridinyl)-1-ethyl-6-fluoro-1,4-dihydro-4- oxo-3-quinolinecarboxylic acid (Example 57A). Example 56F of this patent shows the conversion of 4-(2-methoxy-5-nitrophenyl)-2,6-dimethyl-3,5-pyridinedicarboxylic acid to 4-(2-methoxy-5-nitrophenyl)-2,6-dimethylpyridine by heating it in Dowtherm A. Also, Example 64C shows the conversion of 7-(3,5-dicarboxy-2,6-dimethyl-4-pyridinyl)-1-ethyl-1,4-dihydro-6-methyl-4- oxo-3-quinolinecarboxylic acid to 7-(2,6-dimethyl-4-pyridinyl)-1-ethyl-1,4-dihydro-6-methyl-4-oxo-3-quinolin ecarboxylic acid by heating it in diethyl phthalate at 240.degree.-255.degree. C.
T. Irikura U.S. Pat. No. 4,146,719, issued Mar. 27, 1979, shows as an antibacterial agent 1-ethyl-6-fluoro-1,4-dihydro-4-oxo-7-(1-piperazinyl)-3-quinolinecarboxylic acid, now known as norfloxacin, and its salts.
M. Pesson U.S. Pat. No. 4,292,317, issued Sept. 29, 1981, shows as antibacterial agents 6-halo-1-substituted-7-substituted-amino-1,4-dihydro-4-oxo-3-quinolinecarb oxylic acids and salts thereof, including 1-ethyl-6-fluoro-1,4-dihydro-7-(4-methyl-1-piperazinyl)-4-oxo-3-quinolinec arboxylic acid, now known as pefloxacin.